Bioadhesive polyethylene glycol ointment for medicaments

ABSTRACT

A therapeutic composition having wet adherent properties and particularly useful for delivery of medicaments to mucosal surfaces comprises a therapeutically effective amount of a medicament dispersed in a base material comprising from about 3 to 15% by weight of a water soluble salt of a copolymer of methyl vinyl ether and maleic acid or anhydride and from about 85 to 97% by weight of polyethylene glycol. Formulations of the base material with triamcinolone acetonide and lidocaine are particularly efficacious in the treatment of recurrent aphthous ulcers.

This is a continuation-in-part of application Ser. No. 07/589,666, filedSep. 20, 1990, now U.S. Pat. No. 5,112,620.

FIELD OF THE INVENTION

The present invention relates to therapeutic compositions, and moreparticularly to bioadhesive compositions having wet adherent propertieswhich are suitable for delivery of medicaments to mucosal surfaces andare particularly useful in the treatment of recurrent aphthous ulcers.

BACKGROUND OF INVENTION

Recurrent aphthous ulcers (RAU) or oral canker sores are the most commonoral lesions afflicting humans. Studies have shown such ulcers affect18% to 50% of the general population. As the name suggests, RAU lesionstend to recur in susceptible patients, often lasting for weeks. Theselesions can be characterized as necrotizing ulcerations of oral mucosaltissue which are located on soft, non-keratinized mucosa. The lesionsare painful, affect nutritional intake, and disrupt oral hygiene. Theylead commonly to secondary infections by opportunistic organisms andsometimes result in scarring.

The etiology of RAU has been linked to several causative factorsincluding allergies, trauma, stress, autoimmune dysfunction, nutritionaldeficiencies, microbial infection, hormonal changes, and systemicdisease. However, several studies have shown that whatever the specificetiology in a particular patient, the clinical manifestations of RAU aredue to an altered immune response. Immunosuppressive steroids such astriamcinolone acetonide have been found to be effective in the treatmentof RAU. A problem with steroidal therapy for RAU however, is thatadministration in large doses or over extended periods can cause adrenalsuppression and atrophy. The dosage necessary for steroidal therapy tohave therapeutic effect for RAU can be lessened, thereby decreasing theopportunity and magnitude of harmful side effects, if the therapy isapplied topically rather than systemically. Furthermore, treatmentperiods necessary to achieve the desired therapeutic effect can beshortened if the form of the product encourages patient compliance inapplying the medication on a prescribed schedule.

Several methods of treatment for aphthous ulcers have been explored,including oral tape adhesives and bioadhesive compositions. Forinstance, U.S. Pat. Nos. 4,517,173 to Kizawa et al., 4,765,983 toTakawanagi et al., 4,772,470 to Inoue et al., and 4,876,092 to Mizobuchiet al. all disclose the use of oral tape adhesives. Through clinicalexperience, Applicants have discovered that oral mucosal tapes have verypoor patient compliance. The tapes are awkward to apply, easilydislodged, and are a source of constant irritation and discomfort whenapplied to the oral mucosa.

Other attempts at delivery of medication to the oral mucosa haveincluded bioadhesive compositions based primarily on organic cellulose,such as disclosed in Reissue Patent No. RE.33,093 issued to Schiraldi etal., and polycarbophils disclosed in U.S. Pat. No. 4,615,697 issued toRobinson. The major disadvantages of such compositions is that they areaqueous systems which do not provide as rapid symptomatic relief as thecompositions of the present invention, and which are relatively easilyremoved from the oral mucosa by the flow of saliva.

U.S. Pat. No. 4,948,580 to Browning describes a bioadhesive compositioncomprising a freeze-dried polymer mixture formed of the copolymerpoly(methyl vinyl ether/maleic anhydride) and gelatin dispersed in anointment base such as mineral oil containing dispersed polyethylene. Thefreeze-dried combination of polymer and gelatin is reported to be asynergistic combination having enhanced muco-adhesive propertiescompared to a simple mixture.

The present invention provides a novel and advantageous therapeuticcomposition by combining the therapeutic effect of steroids to counterthe dysfunctional immune response associated with RAU, with a localanesthetic to provide immediate symptomatic relief, in an organic basematerial which provides optimal delivery of the active medications tothe lesions. The base material of the present invention is a bioadhesivecomposition having wet adherent properties which is not readilydisplaced from the oral mucosa even in the presence of saliva, and whichallows the active medications to remain concentrated and localized overthe RAU lesions for an extended treatment period.

It is accordingly an object of the present invention to provide atherapeutic composition for effective local delivery of medicaments tomucosal surfaces. It is a further object of this invention to provide atherapeutic composition for the treatment of recurrent aphthous ulcersby the sustained local delivery of immunosuppressive agents. It is afurther object of this invention to provide a composition for thetopical treatment of RAU by efficiently delivering therapeutic levels ofimmunosuppressive agents to lesions by means of an ointment having wetadherent properties which is not easily removed from oral mucosa in thepresence of saliva. A still further object of this invention is toprovide a therapeutic composition which encourages patient compliance byproviding rapid symptomatic relief to the pain of aphthous ulcers. A yetfurther object of this invention is to provide a novel bioadhesivecomposition useful in formulating therapeutic compositions having wetadherent properties. These and other objects, features and advantages ofthis invention will be apparent to those skilled in the art from theensuing description and examples.

SUMMARY

The compositions of the present invention comprise a therapeuticallyeffective amount of a medicament dissolved in a base material having wetadherent properties in contact with moist mucosal surfaces. The basematerial is a bioadhesive composition comprising from about 3 to 15% byweight of a water-soluble salt of a copolymer of methyl vinyl ether andmaleic acid or anhydride and from about 85 to 97% by weight polyethyleneglycol. The copolymer is preferably a mixed calcium and sodium salthaving a molecular weight of between about 65,000 and 70,000. Thepolyethylene glycol preferably comprises a mixture of a low molecularweight material such as PEG 400 and a higher molecular weight materialsuch as PEG 3350.

Therapeutic compositions of the present invention comprising atherapeutically effective amount of a medicament dispersed in thebioadhesive base material are particularly useful in the treatment ofrecurrent aphthous ulcers wherein the medicament is an immunosuppressivesteroid such as triamcinolone acetonide which is soluble in the PEGcomponent of the base material. The therapeutic composition may alsoinclude a topical anesthetic such as lidocaine to provide immediatesymptomatic relief to the patient. When applied to an aphthous ulcer onthe oral mucosa, the therapeutic composition adheres to the mucosalsurface and delivers the medicament to the area of application over anextended period of time, thereby accelerating the healing rate of theulcer.

DETAILED DESCRIPTION

The therapeutic compositions of the present invention comprise a novelbase material having wet adherent properties and a therapeuticallyeffective amount of one or more medicaments incorporated in said basematerial. The base material is a bioadhesive composition comprising fromabout 3 to 15% by weight of a water soluble salt of a copolymer of alower alkyl vinyl ether and maleic acid or maleic anhydride inpolyethylene glycol (PEG). The PEG preferably comprises a mixture of alow molecular weight PEG which is a liquid at 30° C. and a highmolecular weight PEG which is a waxy solid at 30° C. in proportionswhich result in the mixture having an ointment like consistency at roomtemperature. Suitable mixtures comprise from about 40 to 60% PEG havinga molecular weight of less than 600, most preferably PEG 400, admixedwith about 20 to 50% PEG having a molecular weight above 600, mostpreferably PEG 3350. The PEG component of the bioadhesive compositionmay conform to that described for ointments in the official monograph ofthe U.S. Pharmacopoeia (1990) at page 1963.

The alkyl vinyl ether/maleic acid or anhydride copolymers suitable foruse in the base material are described in U.S. Pat. No. 4,910,247,incorporated herein by reference. In general, these copolymers have fromabout 40 to about 90%, preferably from about 70 to 90%, of the initialcarboxyl groups reacted with a metal, and have a molecular weight ofbetween about 18,000 and about 80,000, preferably between about 40,000and about 60,000 as measured by membrane osmometry in 2-butanone (1-10grams/1000 ml solution). The various metal salts of the copolymer can beprepared by reacting the desired amount of metal hydroxide with a loweralkyl vinyl ether/maleic acid or maleic anhydride copolymer having amolecular weight of from about 18,000 to about 80,000. Such alkyl vinylether/maleic acid or anhydride copolymers are commercially availablefrom GAF Corporation and sold as GANTREZ™ S series (MW approximatelyequal to 18,000-70,000; MS series (MW approximately equal to60,000-75,000) and AN series (MW approximately equal to 18,000-80,000).The resultant metal salt product in which a portion of the originalcarboxyl groups are neutralized, is then dried and milled to a Suitableparticle size.

For purposes of the present invention, the copolymer is preferably ablend comprising a divalent calcium salt and a monovalent sodium salt ofa methyl vinyl ether/maleic acid copolymer wherein the concentration ofCa is between about 10 and 15 wt. % of the blend; the concentration ofNa is between about 1.5 and about 4 wt. % of the blend, and freeacid-COOH represents between about 9 and about 25 wt. % of the blend.Alternatively, a commercially available calcium and sodium salt mixtureof a methyl vinyl ether/maleic acid copolymer can be used in the presentmixture. Such a polymeric salt blend is supplied by GAF Corporation asGANTREZ™ MS-955 wherein the concentration of Ca is between about 11 and13 wt. % of the blend, the concentration of Na is between about 2 and2.5 wt. % of the blend, the proportion of Ca:Na is about 5-6:1 and themolecular weight is about 65,000-70,000.

The medicament incorporated in the therapeutic compositions of thepresent invention may be any therapeutically active agent or combinationof agents useful in the topical treatment of wounds, rashes, ulcers andother conditions. The medicaments are preferably soluble in at least thelow molecular weight PEG component of the base material, since dissolvedmedicaments are generally found to have greater availability and providefaster relief than those which are insoluble and merely dispersed in thebase material. Nevertheless, insoluble dispersed medicaments may besuitable or even preferred for certain treatment applications. While thecompositions of the present invention are particularly useful in thetreatment of aphthous ulcers, the utility of the compositions is not solimited. The compositions of the present invention may also be used inthe topical application of medicaments to other mucous membranes innasal, rectal and vaginal applications as well as oral applications. Inaddition, the compositions of the present invention may be used in thegeneral treatment of wounds, abrasions and other epidermal conditionswhere topical medicaments commonly find application.

By way of illustration, medicaments which may be employed in thetherapeutic compositions of the present invention include antifungalagents such as amphotericin B, nystatin, griseofulvin, miconazole,ketoconazole, econazole, clotrimazole, and other macrolide antifungalagents; antibacterials such as metronidazole, penicillins, monobactams,ampicillin, neomycin, erythromycin, mupirocin, tyrothricin, gramicidin,cephalosporins, gentamycin and other aminoglycosides; antihistaminessuch as chlorpheniramine, diphenhydramine, promethazine,phenylpropanolamine, brompheniramine, doxylamine, tripelennamine,pyrilamine, and triprolidine; anti-cancer agents such as 5-fluorouracil;anti-inflammatory agents such as hydrocortisone; other known steroidssuch as prednisone, prednisolone, triamcinolone, dexamethasone,betamethasone and fluocinonide/fluocinolone acetonide; hemostatic agentssuch as epinephrine, aluminum chloride, ferric chloride, thrombin,collagen, carboxymethylcellulose and oxidized cellulose; hormones suchas oestriol; analgesic and anti-inflammatory agents such asacetaminophen, phenacetin, aspirin, aminopyrine, sulpyrine,phenylbutazone, mefenamic acid, flufenamic acid, ibufenac, ibuprofen,indomethacin, colchicine, and probenecid; and anti-viral agents such asacyclovir, ribavarin, trifluorothyridine or idoxuridine; antisepticssuch as hexachlorophene, tetramethyl thiuramdisulfide, benzalkoniumchloride, cetylpyridium chloride, eugenol, thimerosal, hexylresorcinol,cresols, zinc oxide, methylene blue, boric acid, chloramine-T, gentianviolet, phenyl mercuric chloride, phenyl mercuric nitrate basic,acriflavine, sodium perborate, metallic peroxides such as sodiumperoxide, sodium permanganate, and the halogens. The medicament may bepresent in an amount within the range of from about 0.01 to about 25%and preferably from about 0.05 to about 15% by weight depending upon theparticular medicament employed and the desired site of action.

For the treatment of aphthous ulcers, the medicament is preferably animmunosuppressive steroid such as triamcinolone acetonide which is knownto be effective for this purpose. In addition, the therapeuticcomposition also preferably includes a topical anesthetic such aslidocaine, benzocaine, bupivacaine, cocaine, dyclonine, mepivacaine,procaine, prilocaine, propoxycaine, chloroprocaine, tetracaine or theirhydrochloride salts to provide rapid symptomatic relief to the patient.In a preferred formulation for the treatment of aphthous ulcers, thebase material comprises a mixture of from about 3 to 15% by weightGANTREZ MS-955, from 40 to 60% by weight PEG 400 and 20 to 50% by weightPEG 3350. The active components of the composition comprise from about0.01 to 0.03%, most preferably from about 0.09 to 0.15 by weighttriamcinolone acetonide, and from about 0.25 to 5%, most preferably fromabout 1.5 to 2.5% by weight lidocaine, both of which are soluble in PEG400. Such compositions, when applied to an aphthous ulcer in the oralcavity, are found to adhere well to the mucosal surface and to dissolveslowly in the saliva whereby the medicament is delivered and thetreatment maintained for a period of 15 minutes or longer. In comparisontherewith, compositions based only on the PEG ointment without thecopolymer component do not adhere well to the applied surface anddissolve more rapidly in the saliva, whereby the treatment is effectivefor a period of only a few minutes.

In addition to the active medicaments and anesthetic, the therapeuticcompositions of the present invention may contain other components tomodify the physical or esthetic properties thereof, such as coloringagents, flavoring agents, viscosity modifiers, gelling agents,antioxidants, preservatives and the like. Conventional preservativessuch as methyl paraben and propyl paraben and antioxidants such asbutylated hydroxytolulene and butylated hydroxyanisole are desirablyincluded to prevent bacterial contamination and increase storagestability.

The present invention is illustrated by the following examples directedto the treatment of recurrent aphthous ulcers. For these examples, aseries of therapeutic adhesive compositions were prepared to theformulations set forth below. All parts and percentages are by weightunless otherwise specified.

    ______________________________________                                                Base Material                                                                   GANTREZ       PEG     PEG                                           Formulation                                                                             MS-955        400     3350                                          ______________________________________                                        A         2.4%          47.6%   47.6%                                         B         4.9           51.0    41.9                                          C         5.5           52.2    40.0                                          D         6.0           52.2    39.5                                          E         6.5           52.2    39.0                                          F         7.0           52.2    38.5                                          G         7.5           52.2    38.0                                          H         8.0           52.2    37.5                                          I         10.0          52.5    35.5                                          ______________________________________                                    

All formulations contained the following active components:

2.0% lidocaine

0.1% Triamcinolone acetonide

0.18% methyl paraben-preservative

0.02% propyl paraben-preservative

0.05% butylated hydroxtoluene (BHT)--antioxidant

Therapeutic compositions were prepared for patent evaluation by addingthe BHT to the PEG-400 with heating as necessary to dissolve the BHT.The solution was allowed to cool to approximately 50° C. and the othercomponents added in the following order: GANTREZ, remaining activecomponents, PEG-3350. The mixture was stirred until a uniformconsistency was obtained and allowed to cool to room temperature. Theresulting composition was an ointment which was readily dispensed from acollapsible tube.

The efficacy of the various formulations of the present invention wasdetermined in a series of clinical studies wherein the formulations wereevaluated subjectively for pain relief, healing rate and ease ofapplication by patients afflicted with recurrent aphthous ulcers. Inthese examples, pain was rated 0-5 with 5 being the most severe, healingrate was rated 0-5 with 5 indicating the most rapid rate, and durationof pain was measured as number of days during which the patientexperienced significant discomfort.

On the basis of the clinical studies, it was determined that the GANTREZMS-955 copolymer component is most preferably present in an amount offrom about 4.5 to 7% by weight of the composition. At lowerconcentrations, the wet adherent properties of the composition arediminished, while at higher concentrations the copolymer forms a grainysuspension in the PEG which tends to make the product more difficult toapply and diminishes patient compliance and acceptance.

EXAMPLE 1

A clinical trial was conducted with eight patients who contractedaphthous ulcers at least four times per year. All patients had activeepisodes of aphthous ulcers at the time of the trials. Four subjectswere given Formulation B of the present invention. The other foursubjects were given a commercially available benzocaine ointmentcontaining 20% benzocaine in a denture adhesive-like base as thecontrol. In a subsequent ulcer episode, all eight patients were crossedover so that all patients used both products. Average patient responsein this clinical study is reported in Table I below:

                  TABLE I                                                         ______________________________________                                                 Average Patient Response                                                        Initial      30 min. Healing                                       Treatment  Pain         Pain    Rate                                          ______________________________________                                        Control    4.25         2.25    3                                             Formulation B                                                                            4.75         1.0     4.25                                          Control    4.25         1.75    3.5                                           Formulation B                                                                            4.5          0.75    4.5                                           ______________________________________                                    

The above data demonstrate a significant improvement in both initialpain relief and healing rate for the formulation of this invention ascompared to the commercial benzocaine ointment.

EXAMPLE 2

Clinical trials were performed on 20 patients afflicted with aphthousulcers in a single blind crossover study comparing Formulation C of thepresent invention with a placebo consisting of the same base materialhaving no active components. Ulcers treated were located throughout themouth on the tongue, cheeks, lips and gums. The average patient responsewas as shown in Table II below:

                  TABLE II                                                        ______________________________________                                                 Average Patient Response                                                        Initial    20 min. Duration                                        Treatment  Pain       Pain    of Pain                                         ______________________________________                                        Placebo    4          3.5     3.8(1.5-5.5)                                    Formulation C                                                                            4.2        0.8     1.5(0.5-2.5)                                    ______________________________________                                    

The above data demonstrate that, as expected, no significant pain reliefwas experienced with the placebo treatment, while excellent relief wasprovided by Formula C even 20 minutes after treatment. The averageduration of pain with the Formulation C treatment was furthermorereduced to less than half of that experienced with the placeboindicating a very good healing rate. The range on duration of pain isgiven in parentheses.

EXAMPLE 3

A clinical trial was conducted with 16 patients to compare Formulation Eof the present invention with a commercially available liquidformulation comprising an aqueous solution of CuSO₄, iodine, potassiumiodide and alcohol. Healing time was observed to be shorter for 12 ofthe patients treated with Formulation E and equivalent in the other fourpatients. Greater pain relief with Formulation E was reported by 15 ofthe 16 patients 20 minutes after treatment. Average patient response issummarized in Table III below:

                  TABLE III                                                       ______________________________________                                                 Average Patient Response                                                        Initial    20 min. Duration                                        Treatment  Pain       Pain    of Pain                                         ______________________________________                                        Control    4.1        1.75    2.8(1.5-4.0)                                    Formulation E                                                                            4.1        0.75    1.7(0.5-3.5)                                    ______________________________________                                    

In addition to the improved clinical response experienced by patientswith Formulation E, 15 of the 16 patients also expressed a preferencefor Formulation E in terms of convenience of use.

EXAMPLE 4

A clinical trial was conducted with 12 patients to compare Formulation Fof the present invention with a commercial treatment product comprising0.1% triamcinolone acetonide in an ointment base comprising a mixture ofpectin, gelatin, carboxy methyl cellulose sodium, polyethylene glycoland mineral oil. As in Example 3, the composition of the presentinvention provided superior pain relief and increased healing rate inmost cases and was preferred for use by all 12 patients. Average patientresponse is summarized in Table IV below:

                  TABLE IV                                                        ______________________________________                                                 Average Patient Response                                                        Initial    20 min. Duration                                        Treatment  Pain       Pain    of Pain                                         ______________________________________                                        Control    4.1        2.7     2.5(1.5-3.5)                                    Formulation F                                                                            4.0        0.8     1.5(0.5-2.5)                                    ______________________________________                                    

As demonstrated by the above examples, the present invention provides acomposition for the treatment of recurrent aphthous ulcers whichefficiently delivers immunosuppressive agents to the lesions by topicalapplication to the oral mucosa, and which encourages patient complianceby providing rapid symptomatic relief which endures for at least 20 to30 minutes. Although the invention has been described in conjunctionwith the foregoing specific embodiments, many alternatives, variationsand modifications will be apparent to those of ordinary skill in the artand are included within the spirit and scope of the present invention.Moreover, while the preceding examples have been directed to therapeuticcompositions specifically formulated for the treatment of recurrentaphthous ulcers, it will be appreciated that the medicament deliverycharacteristics afforded by the base material of these formulations canbe utilized in other wound treatment applications, particularly inconjunction with the application of medicaments to mucous membranesurfaces where body fluids have a tendency to wash the medicament fromthe site of treatment. All such applications and methods of treatmentare contemplated by and included in the present invention.

What is claimed is:
 1. A therapeutic composition having wet adherentproperties comprising a base material and a therapeutically effectiveamount of medicament incorporated therein, said base material comprisingfrom about 3 to 15% by weight of a water soluble salt of a copolymer ofa lower alkyl vinyl ether and maleic acid or anhydride and from about 85to 97% by weight of polyethylene glycol (PEG).
 2. The composition ofclaim 1 wherein said copolymer is a sodium salt, a calcium salt, or amixture thereof.
 3. The composition of claim 2 wherein said copolymercomprises a blend of a divalent calcium salt and monovalent sodium saltwherein the concentration of calcium is between about 10 and 15% byweight, the concentration of sodium is between about 1.5 and 4% byweight, and the free acid is between about 9 and 25% by weight.
 4. Thecomposition of claim 3 wherein the copolymer is methyl vinylether/maleic acid and concentration of calcium is between about 11 and13% by weight, the concentration of sodium is between about 2 and 2.5%by weight, the ratio of Ca:Na is about 5-6:1, and the molecular weightof the copolymer is about 65,000-70,000.
 5. The composition of claim 1wherein said polyethylene glycol comprises a mixture of a firstpolyethylene glycol which is a liquid at 30° C. and a secondpolyethylene glycol which is a waxy solid at 30° C.
 6. The compositionof claim 5 wherein said first polyethylene gycol has a molecular weightof less than 600 and said second polyethylene glycol has a molecularweight greater than
 600. 7. The composition of claim 6 comprising fromabout 40 to 60% by weight PEG 400 and from about 20 to 50% by weight PEG3350.
 8. The composition of claim 1 wherein said medicament comprises ananesthetic and asteroid.
 9. The composition of claim 8 wherein saidanesthetic is lidocaine or benzocaine.
 10. The composition of claim 8wherein said steroid is triamcinolone acetonide.
 11. The composition ofclaim 1 wherein said medicament comprises from about 0.25 to 5.0%lidocaine and from about 0.01 to 0.3% triamcinolone acetonide by weightof said composition.
 12. A composition for the topical treatment ofrecurrent aphthous ulcers comprising a therapeutically effective amountof medicament comprising an anesthetic and asteroid effective in thetreatment of said ulcers dispersed in from about 3 to 15% by weight of awater soluble salt of a copolymer of methyl vinyl ether and maleic acidor anhydride, and from about 85 to 97% by weight of polyethylene glycol.13. The composition of claim 12 wherein said steroid is triamcinoloneacetonide.
 14. The composition of claim 13 wherein said triamcinoloneacetonide is present at a concentration of from about 0.01 to 0.3% byweight of said composition.
 15. The composition of claim 14 wherein saidanesthetic is lidocaine present at a concentration of from about 0.25 to5% by weight of said composition.
 16. The composition of claim 15wherein the concentration of said triamcinolone acetonide is from about0.09 to 0.15% and the concentration of said lidocaine is from about 1.5to 2.5% by weight.
 17. The composition of claim 12 wherein saidcopolymer comprises from about 4.5 to 7.0% by weight said composition.18. The composition of claim 12 wherein said copolymer is a sodium salt,a calcium salt, or a mixture thereof.
 19. The composition of claim 18wherein said copolymer comprises a blend of the divalent calcium saltand monovalent sodium salt wherein the concentration of calcium isbetween about 10 and 15% by weight, the concentration of sodium isbetween about 1.5 and 4% by weight, and the free acid is between about 9and 25% by weight.
 20. The composition of claim 19 wherein theconcentration of calcium is between about 11 and 13% by weight, theconcentration of sodium is between about 2 and 2.5% by weight, the ratioof Ca:Na is about 5-6:1, and the molecular weight of the copolymer isabout 65,000-70,000.
 21. The composition of claim 12 wherein saidpolyethylene glycol comprises a mixture of a first polyethylene glycolwhich is a liquid at 30° C. and a second polyethylene glycol which is awaxy solid at 30° C.
 22. The composition of claim 21 wherein said firstpolyethylene glycol has a molecular weight of less than 600 and saidsecond polyethylene glycol has a molecular weight greater than
 600. 23.The composition of claim 22 comprising from about 40 to 60% PEG 400 andfrom about 20 to 50% PEG
 3350. 24. A method for the treatment ofrecurrent aphthous ulcers which comprises topically applying to saidulcers the composition of claim
 12. 25. A method for the treatment ofrecurrent aphthous ulcers which comprises topically applying to saidulcers the composition of claim
 16. 26. A method for the treatment ofrecurrent aphthous ulcers which comprises topically applying to saidulcers the composition of claim
 20. 27. A bioadhesive compositioncomprising from about 3 to 15% by weight of a water-soluble salt of acopolymer of a lower alkyl vinyl ether and maleic acid or anhydride andfrom about 85 to 97% by weight of polyethylene glycol (PEG).
 28. Thecomposition of claim 27 wherein said copolymer is a sodium salt, acalcium salt, or a mixture thereof.
 29. The composition of claim 28wherein said copolymer comprises a blend of a divalent calcium salt andmonovalent sodium salt wherein the concentration of calcium is betweenabout 10 and 15% by weight, the concentration of sodium is between about1.5 and 4% by weight, and the free acid is between about 9 and 25% byweight.
 30. The composition of claim 29 wherein the copolymer is methylvinyl ether/maleic acid and concentration of calcium is between about 11and 13% by weight, the concentration of sodium is between about 2 and2.5% by weight, the ratio of Ca:Na is about 5-6:1, and the molecularweight of the copolymer is about 65,000-70,000.
 31. The composition ofclaim 27 wherein said polyethylene glycol comprises a mixture of a firstpolyethylene glycol which is a liquid at 30° C. and a secondpolyethylene glycol which is a waxy solid at 30° C.
 32. The compositionof claim 31 wherein said first polyethylene glycol has a molecularweight of less than 600 and said second polyethylene glycol has amolecular weight greater than
 600. 33. The composition of claim 32comprising from about 40 to 60% by weight PEG 400 and from about 20 to50% by weight PEG 3350.